酸性预适应激活钠-氢交换体1调控细胞内pH稳态减轻肾缺血再灌注损伤的研究

doi:10.12114/j.issn.1007-9572.2024.0105

中国全科医学 ›› 2026, Vol. 29 ›› Issue (12): 1607-1617.DOI: 10.12114/j.issn.1007-9572.2024.0105

酸性预适应激活钠-氢交换体1调控细胞内pH稳态减轻肾缺血再灌注损伤的研究

陈安南¹^,²^,³, 颜芷昕¹^,²^,³, 张健¹^,²^,³, 沈波¹^,²^,³, 丁小强¹^,²^,³^,^*(), 宋娜娜¹^,²^,³^,^*()

1．200032　上海市，复旦大学附属中山医院肾内科
2．201203　上海市肾脏疾病与血液净化重点实验室
3．201203　上海市复旦大学张江研究所

收稿日期:2025-01-10 修回日期:2025-08-25 出版日期:2026-04-20 发布日期:2026-03-12
通讯作者: 丁小强, 宋娜娜
作者贡献：
丁小强、宋娜娜提出研究设想；陈安南、颜芷昕、张健、沈波参与实验设计，负责实验实施，观测指标的测量，数据收集和统计学分析；陈安南、宋娜娜负责撰写文章初稿；丁小强、宋娜娜负责文章的质量控制和审校；所有作者确认了最终稿。
基金资助:
国家自然科学基金资助项目(82070710); 2021年度上海市科技创新行动计划-生物医药科技支撑专项（中医专项）(21S21902900)

Acidic Preconditioning Activates the Sodium-hydrogen Exchanger 1 to Regulate Intracellular pH Homeostasis and Reduce Renal Ischemia-reperfusion Injury

CHEN Annan¹^,²^,³, YAN Zhixin¹^,²^,³, ZHANG Jian¹^,²^,³, SHEN Bo¹^,²^,³, DING Xiaoqiang¹^,²^,³^,^*(), SONG Nana¹^,²^,³^,^*()

1. Department of Nephology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
2. Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai 201203, China
3. Fudan Zhang Jiang Institute, Shanghai 201203, China

Received:2025-01-10 Revised:2025-08-25 Published:2026-04-20 Online:2026-03-12
Contact: DING Xiaoqiang, SONG Nana

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摘要/Abstract

摘要： 背景适宜的细胞内pH（pHi）是细胞发挥功能的基础。酸性预处理有利于诱导细胞内液酸适应，增强细胞应对损伤性应激的能力，被称为酸性预适应（AP）。钠-氢交换体1（NHE1）在肾小管上皮细胞广泛表达，也是细胞排H+的主要通道之一。然而，NHE1在肾脏AP中的作用及其机制尚不明确。目的本研究首先在人肾小管上皮细胞系（HK2）中建立可有效减轻缺氧/复氧（H/R）损伤的AP模型，围绕NHE1阐明AP调控pHi稳态的作用机制，并在小鼠缺血预适应（IPC）模型中加以验证。方法实验于2023年6—12月在复旦大学附属中山医院肾内科实验室完成。在体外实验，采用缺氧24 h后复氧1 h建立HK2细胞的H/R模型。应用pH 6.6酸性培养基处理细胞，构建AP模型。根据不同实施方案分为3部分，（１）AP模型的建立：将AP过程分为pH 6.6酸性培养基处理阶段（A）和pH 7.4正常培养基恢复阶段（R），HK2细胞先后经过不同时间的A和R处理后再进行H/R，探索最佳AP模型及其对NHE1和pHi的调控作用；（2）使用NHE1的小干扰RNA（siNHE1）敲低NHE1，观察AP保护效应的改变；（3）应用低氯离子培养基抑制pHi的波动，观察AP对NHE1调控作用和保护效应的改变。在体内实验，选取24只SPF级雄性野生型C57BL/6小鼠，分为假手术组（Sham组）、肾缺血再灌注组（I/R组）、肾缺血预适应组（IPC组）、肾缺血预适应+肾缺血再灌注组（IPC+I/R组），每组各6只。I/R模型采用夹闭双侧肾动静脉35 min后复灌流24 h。IPC模型采用夹闭双侧肾动静脉15 min后复灌流4 d。IPC+I/R组则是在IPC后进行I/R处理。使用CellTiter-Lumi Ⅱ发光法检测细胞活力。使用Western Blotting法检测NHE1、活化型半胱氨酸天冬氨酸蛋白酶（cleaved caspase）3、肾脏损伤分子1（KIM1）和cleaved caspase 9表达水平；使用流式细胞仪和Tunel染色评估细胞凋亡水平；采用BCECF-AM探针和NH4Cl冲击法检测pHi和NHE1活力；采用细胞外液pH值（pHe）-pHi曲线评估pHi稳态维持能力；使用免疫荧光染色检测NHE1在HK2细胞和肾脏组织中的定位。结果酸性处理12 h，正常培养基恢复6 h可显著降低H/R处理后cleaved caspase 3和cleaved caspase 9表达水平，减少Annexin V和Tunel阳性细胞比例（P<0.05）。AP缓解H/R处理后的细胞内酸化（P<0.05），上调NHE1表达和活性，并上移pHe-pHi曲线；敲减NHE1表达下移AP后的pHe-pHi曲线。敲减NHE1减弱AP对H/R损伤的保护作用，表现为cleaved caspase 3和cleaved caspase 9表达水平升高（P<0.05）。低氯培养消除了AP早期pHi的波动，同时抑制了AP后NHE1表达上调和pHe-pHi曲线上移。IPC缓解I/R后的pHi降低（P<0.05）并上移pHe-pHi曲线。IPC显著降低了I/R后KIM1和cleaved caspase 3表达水平，上调I/R后NHE1表达水平（P<0.05）。免疫荧光显示I/R后NHE1在近端肾小管上皮细胞表达增多。结论本研究在肾脏细胞H/R模型中证实AP的保护作用。AP通过诱导pHi的短暂波动上调NHE1表达和活性，进而诱导细胞内酸适应，最终减轻H/R损伤。

关键词: 急性肾损伤, 酸性预适应, 缺血预适应, 钠-氢交换体1, 细胞内pH

Abstract:

Background

Appropriate intracellular pH is essential for the proper functioning of cells. Acidic pretreatment can induce intracellular acidic adaptation and improve cells' ability to withstand harmful stress, a process known as acidic preconditioning (AP). Sodium-hydrogen exchanger 1 (NHE1) is commonly found in renal tubular epithelial cells and serves as a key channel for the excretion of H⁺. Nevertheless, the role of NHE1 in renal AP are still not fully understood.

Objective

This study developed an AP model in the human renal tubular epithelial cell line (HK2) that effectively mitigates hypoxia/reoxygenation (H/R) injury. The research also clarified the mechanism of AP in regulating pHi homeostasis via regulating NHE1, which was further validated in a mouse ischemic preconditioning(IPC) model.

Methods

The experiment was conducted from June to December 2023 at the Laboratory of Nephrology, Zhongshan Hospital, Fudan University. HK2 cells were subjected to hypoxia for 24 hours and then reoxygenation for 1 hour to establish an in vitro model of acute kidney injury(AKI); C57BL/6 mice were performed 35 minutes occlusion of bilateral renal artery following reperfusion for 24 hours to establish in vivo model of AKI; Mice were clamped on both sides of the renal artery for 15 minutes and then perfused for 4 days since I/R. C57BL/6 mice were randomly divided into sham group (Sham), IPC group, I/R group and IPC+I/R group, n=6 in each group, among which the mice in the IPC+I/R group referred to bilateral renal arteries of the mice were occluded for 15 minutes and then perfused for 4 days before I/R was performed. The in vitro experiment was divided into three parts. Part 1: to establish the AP model, HK-2 cells were treated with pH 6.6 acidic medium (A) followed by pH 7.4 normal medium (R) before subjecting them to H/R. Part 2: small interfering RNA against NHE1 (siNHE1) was used to knock down NHE1 expression; Part 3: HK2 cells were treated with low chloride medium at pH 6.6 in phase A and normal chloride medium at pH 7.4 in phase R. Cell viability was evaluated using the CellTiter-Lumi luminescence method, apoptosis levels were assessed through Western Blotting, Tunel staining, and Annexin V-FITC/PI double staining. The activity of NHE1 and pHi were detected by BCECF-AM probe and NH4Cl-prepulse technology. The ability of maintenancing steady-state of pHi was evaluated by extracellular pH(pHe)-pHi curve, and the expression of NHE1 was detected through immunofluorescence in kidney tissue and HK2 cells.

Results

Treatment with acidic conditions for 12 hours and subsequent recovery in normal medium for 6 hours significantly decreased the expression levels of cleaved caspase 3 and cleaved caspase 9 following hypoxia/reoxygenation (H/R) treatment, as well as reduced the proportion of Annexin V and Tunel positive cells (P<0.05). Furthermore, AP mitigated intracellular acidification post H/R treatment (P<0.05), increased NHE1 expression and activity, and shifted the pHe-pHi curve upwards; silencing NHE1 expression resulted in a downward shift of the pHe-pHi curve after AP treatment. Knocking down NHE1 attenuated the protective effects of AP against H/R injury, leading to higher expression levels of cleaved caspase 3 and cleaved caspase 9 (P<0.05). Treatment with low-chloride medium abolishes the impact of acidic stimulation on pHi, while also reversing the upregulation of NHE1 expression and the upward shift of the pHe-pHi curve post AP (P<0.05). There was a decrease in pHi fluctuations after ischemia/reperfusion (I/R) (P<0.05) and an upward shift in the pHe-pHi curve after IPC. IPC also significantly decreased the expression levels of KIM1 and cleaved caspase 3, while upregulating NHE1 expression after I/R (P<0.05). Additionally, IPC facilitated the colocalization of NHE1 and LTL after I/R.

Conclusion

AP promotes the maintenance of pHi homeostasis by increasing NHE1 expression and activity via transient fluctuations in pHi, leading to intracellular acidic adaptation and mitigating H/R injury.

Key words: Acute kidney injury, Acidic preconditioning, Ischemic preconditioning, Sodium-hydrogen exchanger 1, Intracellular pH

中图分类号:

R 692

陈安南,颜芷昕,张健,等. 酸性预适应激活钠-氢交换体1调控细胞内pH稳态减轻肾缺血再灌注损伤的研究[J]. 中国全科医学, 2026, 29(12): 1607-1617. DOI: 10.12114/j.issn.1007-9572.2024.0105.
CHEN Annan,YAN Zhixin,ZHANG Jian, et al. Acidic Preconditioning Activates the Sodium-hydrogen Exchanger 1 to Regulate Intracellular pH Homeostasis and Reduce Renal Ischemia-reperfusion Injury[J]. Chinese General Practice, 2026, 29(12): 1607-1617. DOI: 10.12114/j.issn.1007-9572.2024.0105.

图/表 22

图1 不同时间A和R处理后HK2细胞在H/R损伤后cleaved caspase 3和cleaved caspase 9蛋白检测结果（n=6）注：a表示R固定为3 h，A1、A6、A12、A24、A48分别表示培养处理1、6、12、24、48 h后；b表示A固定为12 h，R0、R3、R6、R12分别表示恢复时间为0、3、6、12 h；cleaved caspase=活化型半胱氨酸天冬氨酸蛋白酶，H/R=缺氧/复氧。

Figure 1 Results of cleaved caspase 3 and cleaved caspase 9 protein detection in HK2 cells treated with A and R at different times after H/R injury

图2 当酸性培养基处理时间为12 h，正常培养基恢复时间为6 h，HK2细胞H/R损伤后Tunel染色结果注：AP=缺血预适应。

Figure 2 Results of Tunel staining of HK2 cells after H/R injury，when the acidic medium treatment time is 12 h and the normal medium recovery time is 6 h

图3 当酸性培养基处理时间为12 h，正常培养基恢复时间为6 h，HK2细胞H/R损伤后Annexin V/PI检测结果注：PI=碘化丙啶。

Figure 3 Results of Annexin V/PI detection of HK2 cells after H/R injury when the acidic medium treatment time is 12 h and the normal medium recovery time is 6 h

表1 不同时间A和R处理后的HK2细胞在H/R损伤后的细胞活力比较（±s）

Table 1 Comparison of cell viability of HK2 cells treated with A and R at different times after H/R injury

组别	只数	细胞活力
对照组	6	96.911±7.909
H/R组	6	9.364±1.304^a
H/R+A1R3组	6	13.810±3.078
H/R+A6R3组	6	10.620±1.583
H/R+A12R3组	6	19.638±3.502^ab
H/R+A24R3组	6	11.132±1.405
H/R+A12R6组	6	35.595±4.664^bc
H/R+A12R12组	6	7.642±1.676
F值		380.281
P值		<0.001

表2 不同时间A和R处理后的HK2细胞在H/R损伤后的cleaved caspase 3和cleaved caspase 9蛋白表达水平（±s）

Table 2 Expression of cleaved caspase 3 and cleaved caspase 9 protein in HK2 cells treated with A and R at different time points after H/R injury

组别	只数	cleaved caspase 3	cleaved caspase 9
对照组	4	1.198±0.462	1.061±0.169
H/R组	4	4.620±0.283^a	2.865±0.441^a
H/R+A1R3组	4	4.337±0.363	2.583±0.393
H/R+A6R3组	4	3.953±0.410	2.402±0.335
H/R+A12R3组	4	2.422±0.176^ab	1.460±0.287^ab
H/R+A24R3组	4	3.968±0.715	3.006±0.712
H/R+A48R3组	4	4.389±0.763	2.973±0.425
H/R+A12R0组	4	4.377±0.386	4.781±0.551
H/R+A12R6组	4	1.740±0.285^ac	2.099±0.260^ac
H/R+A12R9组	4	3.545±0.250	3.545±0.157
H/R+A12R12组	4	3.726±0.523	4.405±0.417
F值		19.673	22.786
P值		<0.001	<0.001

表3 当酸性培养基处理时间为12 h，正常培养基恢复时间为6 h，HK2细胞H/R损伤后Tunel阳性细胞比例和Annexin V阳性细胞比例（±s）

Table 3 The proportion of Tunel-positive cells and the proportion of Annexin V-positive cells in HK2 cells after H/R injury when the acidic medium treatment time is 12 h and the normal medium recovery time is 6 h

组别	只数	Tunel阳性细胞比例	Annexin V阳性细胞比例
对照组	4	0.811±0.201	4.882±1.099
H/R组	4	55.348±2.585^a	26.268±5.151^a
H/R+AP组	4	21.716±3.404^b	9.986±1.050^b
F值		124.042	14.066
P值		<0.001	<0.001

图4 经AP处理的HK2细胞在H/R损伤后的复氧阶段的pHi动态改变注：红色垂直线表示AP处理后的HK2细胞的pHi在H/R后恢复至正常水平的时间点为30 min，灰色垂直线表示未处理的HK2细胞的pHi在H/R后恢复至正常水平的时间点大约是90 min；pHi=细胞内pH。

Figure 4 Dynamic changes in pHi of AP-treated HK2 cells during the reoxygenation after H/R injury

表4 AP处理的HK2细胞在H/R损伤前后的pHi（±s）

Table 4 pHi of AP-treated HK2 cells before and after H/R injury

组别	只数	pHi
对照组	4	7.304±0.031
H/R组	4	6.842±0.041^a
H/R+AP组	4	7.000±0.094^b
F值		85.577
P值		<0.001

图5 敲低NHE1表达后的HK2细胞的pHe-pHi曲线注：pHe=细胞外液pH值。

Figure 5 The pHe-pHi curve of HK2 cells after knockdown of NHE1 expression

表5 敲低NHE1表达后的HK2细胞的NHE1通道活性（±s）

Table 5 NHE1 activity of HK2 cells after knockdown of NHE1 expression

组别	只数	NHE1活性（dpHi/dt）	NHE1表达量
Scramble组	3	0.133±0.017	0.997±0.028
siNHE1组	3	0.021±0.003^a	0.309±0.042^a
AP组	3	0.240±0.003^ab	3.393±1.537^ab
AP+siNHE1组	3	0.031±0.021^ac	0.330±0.032^ac
F值		41.811	14.135
P值		<0.001	<0.001

图6 经AP和siNHE1处理后的HK2细胞在H/R损伤后NHE1、cleaved caspase 3和cleaved caspase 9蛋白检测结果。

Figure 6 Results of NHE1，cleaved caspase 3 and cleaved caspase 9 protein detection in HK2 cells treated with AP and siNHE1 after H/R injury

表6 经AP和siNHE1处理后的HK2细胞在H/R损伤后NHE1、cleaved caspase 3和cleaved caspase 9蛋白表达水平（±s）

Table 6 Expression of NHE1，cleaved caspase 3 and cleaved caspase 9 protein in HK2 cells treated with AP and siNHE1 after H/R injury

组别	只数	cleaved caspase 3	cleaved caspase 9	NHE1
对照组	4	1.000±0.081	1.000±0.072	1.000±0.048
siNHE1组	4	0.859±0.274	0.931±0.400	0.311±0.039
H/R组	4	5.264±0.635^a	6.982±0.439^a	1.219±0.173
AP组	4	1.127±0.257	1.026±0.171^b	3.036±0.642
AP+siNHE1组	4	1.307±0.369	1.102±0.072^b	0.372±0.087
H/R+ siNHE1组	4	4.641±0.434^a	6.561±0.459^a	0.417±0.093
H/R+AP组	4	1.854±0.492^ab	3.711±0.754^ab	3.258±0.629
H/R+AP+ siNHE1组	4	4.075±0.422^ac	5.612±0.216^ac	0.401±0.064
F值		82.539	190.997	65.973
P值		<0.001	<0.001	<0.001

图7 HK2细胞中NHE1和Paxillin的荧光染色结果注：绿色荧光表示Paxillin，红色荧光表示NHE1，蓝色荧光表示细胞核，白色方框表示共定位区域。

Figure 7 Results of immunofluorescence staining of NHE1 and Paxillin in HK2 cells

图8 HK2细胞在酸性和低氯培养基处理后pHi的动态变化

Figure 8 Dynamic changes in pHi of HK2 cells after treatment with acidic culture medium

图9 低氯培养的HK2细胞在AP处理后NHE1蛋白检测结果

Figure 9 Results of NHE1 protein detection in HK2 cells cultured in low chlorine solution after AP

图10 低氯培养的HK2细胞在AP处理后的pHe-pHi曲线

Figure 10 The pHe-pHi curve of HK2 cells cultured in low chlorine solution after AP

表7 低氯培养的HK2细胞在AP处理后NHE1蛋白表达水平（±s）

Table 7 Expression of NHE1 protein in HK2 cells cultured in low chlorine solution after AP

组别	只数	NHE1表达量	NHE1活性（dpHi/dt）
对照组	4	1.000±0.154	0.387±0.036
AP组	4	5.072±0.164^a	0.685±0.207^a
低氯培养组	4	0.925±0.157^b	0.381±0.059^b
AP+低氯培养组	4	1.318±0.277^b	0.388±0.049^b
F值		422.575	5.371
P值		<0.001	0.026

图11 IPC处理后的小鼠在I/R后NHE1、KIM1和cleaved caspase 3蛋白检测结果

Figure 11 Results of NHE1，KIM1 and cleaved caspase 3 protein detection in mices treated with IPC after I/R

图12 小鼠肾脏石蜡切片NHE1免疫荧光染色结果注：绿色荧光表示NHE1，黄色荧光表示LTL，蓝色荧光表示细胞核。

Figure 12 Results of NHE1 immunofluorescence staining of mouse kidney paraffin sections

图13 小鼠肾脏细胞的pHe-pHi曲线

Figure 13 The pHe-pHi curve of mice kidney cells

表8 IPC处理后的小鼠在I/R后NHE1、KIM1和cleaved caspase 3蛋白表达水平（±s）

Table 8 Expression of NHE1，KIM1 and cleaved caspase3 protein in mices treated with IPC after I/R

组别	只数	NHE1	cleaved caspase 3	KIM1
sham组	6	1.044±0.103	1.000±0.151	1.000±0.285
IPC组	6	1.041±0.392^a	2.858±0.369	0.859±0.285
I/R组	6	1.774±0.392	3.580±0.413^a	9.797±0.954^a
IPC+I/R组	6	2.858±0.485^b	1.828±0.489^b	3.868±0.345^b
F值		39.265	60.199	323.384
P值		<0.001	<0.001	<0.001

表9 小鼠肾脏组织pH和肾脏细胞pHi（±s）

Table 9 pH of mice kidney tissue and pHi of mice kidney cells

组别	只数	肾脏组织pH	肾脏细胞pHi
sham组	4	7.389±0.096	7.476±0.103
I/R组	4	6.073±0.096^a	7.286±0.073^a
IPC+I/R组	4	6.088±0.169	7.304±0.031^b
F值		17.386	10.521
P值		<0.001	<0.001

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酸性预适应激活钠-氢交换体1调控细胞内pH稳态减轻肾缺血再灌注损伤的研究

Acidic Preconditioning Activates the Sodium-hydrogen Exchanger 1 to Regulate Intracellular pH Homeostasis and Reduce Renal Ischemia-reperfusion Injury

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